Hitherto, it was known that 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate compounds exhibit interesting pharmacological activities such as vasodilation and blood pressure lowering activities as disclosed in, for example, Naturwissenschaften, 58, 578 (1972); J. Pharm. Pharmacol., 24, 917 (1972); Arnzeim.-Forsch., 22, 1 (1971); Arzneim.-Forsch., 30, 2144 (1980); J. Pharm. Sci., 62, 580 (1973); J. Med. Chem., 17, 956 (1974); Belgian Patent No. 689,377; U.S. Pat. No. 3,485,847. Of these known compounds, dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate disclosed in the above U.S. Pat. No. 3,485,847 is now commercially available under the general name of "nifedipine" as a coronary vasodialtor. However, nifedipine is still unsatisfactory in the duration of its vasodilating activity and its side-effects.
Further nifedipine is extremely unstable to light and such defect causes various problems in preparing pharmaceutical preparations containing nifedipine, as reported in Kiso To Rinsho (Tokyo), 6, 259 (1972); Arzneim.-Forsch., 28, 2188 (1978); Yakugaku Zasshi, 101, 1149 (1981), etc.
Under such circumstances, various attempts have been made to develop 1,4-dihydropyridine-3,5-dicarboxylate derivatives having higher pharmacological activities and light-stability and lower side-effects and such derivatives have been proposed in, for examples, German OLS Nos. 2,747,513, 2,841,667, 2,847,237, 2,921,429, 2,847,236, 1,963,188, 1,923,990, 2,117,571, 2,117,573, 2,005,116, 2,218,644 and 2,549,568; and Japanese Patent Publication (Unexamined) Nos. 84576/75, 101365/75, 131970/75, 40576/75, 12632/76, 95976/78, 9083/80, 40678/80, 127356/81, etc.
However, most of the compounds disclosed in the above prior art references would still require further improvements in their pharmacological activities, absorption from gastro-intestinal tracts, side-effects, toxicity and/or light-stability.
As a result of extensive studies to overcome the disadvantages of these known 1,4-dihydropyridine compounds, the present inventors found that the 1,4-dihydropyridine compounds represented by the formula (I) above exhibit markedly excellent properties in every aspects and completed the present invention.
Surprisingly, the 1,4-dihydropyridine compounds of the formula (I) according to the present invention possess markedly strong coronary and vertebral artery vasodilating activity, blood pressure lowering activity and antihypertensive activity and, hence, they are useful as pharmaceutical agent for prevention and treatment of ischemic cardiac failure, cerebral circulation disturbance, hypertension and/or the complication of these disorders. In addition, these compounds are of low toxicity and stable to light.
It was also known that 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate derivatives can be prepared by a so-called Hantzsch reaction or modifications thereof, i.e., by the reaction between a benzylidineacetoacetate derivative and a .beta.-aminocrotonate derivative or between benzylideneacetoacetate, an acetoacetate derivative and ammonia as disclosed in, for example, Ann., 215, 1 (1882), Ber., 15, 2914 (1882); ibid, 17, 1521 (1884); ibid, 17, 2903 (1884); ibid, 20, 1338 (1887); ibid, 31, 743 (1898); J. Chem. Soc., 413 (1943); J. Amer. Shem. Soc., 71, 4003 (1949); J. Org. Chem., 30, 1914 (1965). The 1,4-dihydropyridine compounds of the formula (I) can also be prepared easily according to a conventional procedure from commercially available starting materials as hereinafter described in detail.